The overall objectives are the development of new antiviral drugs targeted to inhibit HIV-1 sites different from those targeted by currently available drugs. The specific aim of this proposal is to design compounds which inhibit the biding of HIV-1 RT with Template- Primer DNA (T-P DNA), a prerequisite step in HIV-1 replication. T- P DNA binds to a highly conserved region, 2 Helix H, of HIV-1 RT. Recently, a natural product 3,5,8-tribhydroxy-4- quinoline (THQ), from a marine sponge, was shown to inhibit the binding of T-P DNA with HIV-1 RT. However, THQ was unstable when exposed to air. In preliminary studies, the applicant has synthesized several carbocyclic analogs of THQ as lead compounds, which were more stable than THQ, and some of which were also more effective inhibitors of HIV-1 RT and of the replication of HIV-1 in lymphocyte cultures. This application describes the synthesis of isosteres and congeners of these lead compounds, the evaluation of their quantitative structure-activity relationships, and identification of the most promising drug candidates which may be effective against HIV-1, either per se, or in combination with currently available drugs. There is an excellent commercial potential for antiviral drugs for which escape mutants are less likely due to the highly conserved nature of the target.